Anemia in burn patients is largely multifactorial requiring multiple transfusions. Emerging evidences around the globe indicate transfusion risks outweigh benefits in the critically ill. Transfusions greater than four units of blood are an independent risk factor for morbidity, mortality and systemic infections in burn patients. Reduced erythrocyte production due to lack of erythropoietin (Epo) could contribute to anemia. Nevertheless, unlike in patients with kidney failure and patients after chemotherapy, Epo administration to burn patients fails to alleviate anemia. Our recent studies demonstrate that resistance to Epo in experimental burn is due to decrease in the number of bone marrow erythroid progenitors and that beta-adrenergic blockade following burn significantly improves the bone marrow erythroid cells. We have also established that burn injury offsets the balance between erythroid specific and monocyte specific transcription factors in multi potent stem cells. Taken together, our overarching hypothesis states that post burn anemia of critical illness is due to impaired erythropoiesis, which is orchestrated by a combination of dysregulated hematopoietic transcription factors and burn environment. We seek to test this hypothesis through the 3 specific aims. In aim 1) we will study the transcriptional regulation of impaired lineage commitments causing anemia of critical illness post burn with and without beta-blockade. First, we will delineate the role of hemopoietic transcription factors MafB and GATA-1 in regulating the impairment of bone marrow erythropoiesis after burns through intervention using loss of function and gain of expression studies and later evaluate the gain of Epo responsiveness after beta-blocker treatment. In aim 2) we will investigate the signaling mechanisms that determine impaired erythroid commitments following burn injury where, the intracellular signaling mediators that inhibit erythroid commitment and promote monocyte commitments will be addressed. We will define the crosstalk between lineage commitment associated cell signals and the catecholamine mediated signals following burn injury in an attempt to restore the erythroid progenitor differentiation in hemopoietic stem and progenitor cells. In aim 3) we will interrogate temporal and mechanistic defects during erythropoietic development in burn patients and evaluate the efficacy of beta-blockade where we will establish that PBMC derived erythroid progenitors and the sequential distribution of erythroblast sub sets are disrupted following burn as a read out to bone marrow erythropoiesis. Next, we will evaluate the balance between MafB and GATA-1 expressions and the signaling mechanisms that dictate PBMC derived CD34+ hematopoietic stem cells and erythroid progenitors from burn patients with and without beta-blockade. Results gleaned from the experimental model combined with clinical data will provide the mechanistic insight into post burn anemia, which will pave the way for potential therapeutic interventions to treat anemia of critical illness.